An Association Between a Functional Variant of the MET Gene and the Presence of Maternal Anti-Fetal Brain Antibodies

Background: Autism Spectrum Disorder (ASD) is a highly heritable disorder. However, few causative mechanisms have been described for these genetic perturbations. Recently, a functional polymorphism in the MET gene (‘C’ allele of rs1858830) was associated with autism risk in three independent samples (P<1x10-6). The MET ‘C’ allele disrupts gene transcription and results in a ~2 fold decrease in the expression of the gene product, the MET receptor tyrosine kinase.  MET signaling is involved in a number of physiological processes that are relevant to autism risk, including the formation and maturation of neural circuitry and negative regulation of immune responses. An independent line of research revealed that a subset of mothers of children with autism exhibit an inappropriate immune response in the form of antibodies directed against specific fetal brain proteins. A pattern of two specific maternal autoantibody bands, at 37 kDa and 73 kDa, was specific to mothers of children with autism. We hypothesized that mothers who are carriers of the MET ‘C’ allele may have an increased incidence of fetal-brain autoantibodies as a result of altered immune system regulation.

Objectives: To examine association of MET rs1858830 genotype with the presence of maternal antibodies directed against fetal brain proteins.

Methods: Genotypes at the MET rs1858830 locus were determined by direct re-sequencing.  In addition, plasma from all mothers was analyzed by western blot for the presence of antibodies directed against specific fetal brain antigens. The presence of a 37 and 73 kDa band was then correlated with the MET rs1858830 genotype.
Results: 100% of AU mothers harboring both the 37 and 73 kDa bands also had either the MET C/C or C/G genotype while none of the control mothers had this antibody pattern (P=0.005). Further, analysis of MET ‘C’ allele association with the 37 kDa band alone in the mothers with children with autism also revealed a significant association (P=0.003). There was no association of the MET ‘C’ allele with the 73 kDa band alone.

Conclusions: These results suggest that the presence of the MET ‘C’ allele in mothers of children with autism may increase susceptibility to immune dysregulation and the consequent generation of antibodies directed towards fetal brain proteins.  Specific hypotheses will be tested concerning the functional effect of the MET gene variant on negative regulation of immune responses in mothers of children with autism.